Derangements in the CHGA (chromogranin A) pathway are associated with hypertensive renal disease, a devastating illness found principally in African Americans. During studies of the CHGA gene in African Americans, we have developed evidence for a novel, sequential pathway of events whereby common genetic variation in the 3'-UTR of the mRNA sets off a pathogenic cascade: CHGA 3'-UTR C+87T (rs7610) disrupts a small/non-coding RNA recognition motif (micro-RNA hsa-miR-107), to alter CHGA mRNA translation, eventuating in a decrease in formation of the catestatin (catecholamine release inhibitory) peptide, in association with hypertensive ESRD. Recently we have been able to stabilize synthetic catestatin against degradation, using a Retro-Inverso (R-I) peptidomimetic strategy. Strategy in this proposal, we will explore two points in this sequential pathway - the CHGA 3'-UTR polymorphism and the catestatin peptide - in an attempt to develop pharmacological probes that could eventuate in novel therapeutic approaches. We have already developed compelling preliminary data (proof of principle) for each Aim. The aims give rise to testable hypotheses that can be confirmed or refuted by the experiments outlined. Aim-1: CHGA mRNA 3'-UTR micro-RNA motif. We will characterize the human 3'-UTR CHGA polymorphism C+87T (rs7610) and how it disrupts micro-RNA (hsa-miR-107) recognition. We anticipate that this step will elucidate the trigger for decline in catestatin formation, and sugget logical interventions. Aim-2: CHGA fragment catestatin peptidomimetics. We will characterize stable synthetic variants of a positive (or rescue) feature of the cascade: the CHGA peptide catestatin, including its recently synthesized, stable Retro-Inverso (R-I) mimetic. Here we anticipate achieving enhanced activity, stability, and duration of action. Significance these two Aims emerge from a novel pathogenic pathway developed for a disease state of importance to NIDDK. We therefore anticipate that our studies should provide new inroads into therapeutic approaches for a currently intractable health disparity. The proposal thus represents an opportunity to define the genetic basis of a pathogenic pathway, its mechanistic consequences, and its role in risk for development of an important human disease. PUBLIC HEALTH RELEVANCE: The proposal represents an opportunity to define the contribution of the chromogranin/secretogranin system to a major clinical problem: hypertensive kidney disease in minority populations such as African Americans. Our studies probe the mechanism whereby genetic variation may eventuate in the disease, and a novel potential therapeutic inroad into the syndrome; our initial results suggest novel pathophysiological links between genetic variation at an adrenergic gene, and risk for hypertensive nephrosclerosis. The findings should suggest new strategies to approach the mechanism, diagnosis, treatment, and complications of this common yet so far poorly understood disorder.